Artificial, flexible valves and methods of fabricating and serially expanding the same

ABSTRACT

One aspect of the invention provides and artificial, flexible valve indlucding: a stent defining a wall and a plurality of leaflets extending from the wall of the stent. The plurality of leaflets form a plurality of coaptation regions between two adjacent leaflets. The coaptation regions include extensions along a z-axis and adapted and are configured to form a releasable, but substantially complete seal when the leaflets are in a closed position. Another aspect of the invention provides an artificial, flexible valve including: a stent defining a wall and a plurality of leaflets extending from the wall of the stent. Each of the plurality of leaflets terminates in a commissure line. The commissure lines devi-ate from a hyperbola formed in the x-y plane by at least one deviation selected from the group consisting of: a deviation in the z-direction and one or more curves relative to the hyperbola.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 61/989,820, filed May 7, 2014. The entire content of thisapplication is hereby incorporated by reference herein.

BACKGROUND OF THE INVENTION

Valves exist in the body (e.g., in the heart and the systemic veins) toallow unidirectional blood flow. A variety of congenital conditions,infectious diseases (e.g., rheumatic heart disease), endocarditis, andage-related impairments (e.g., senile stenosis) can necessitateimplantation of an artificial valve.

SUMMARY OF THE INVENTION

One aspect of the invention provides an artificial, flexible valveincluding: a stent defining a wall and a plurality of leaflets extendingfrom the wall of the stent. The plurality of leaflets form a pluralityof coaptation regions between two adjacent leaflets. The coaptationregions include extensions along a z-axis and adapted and are configuredto form a releasable, but substantially complete seal when the leafletsare in a closed position.

This aspect of the invention can have a variety of embodiments. Theextensions can have a length along the z-axis between about 1 mm andabout 10 mm. The extensions can have a curved profile. The curvedprofile can lie in an x-y plane. The curved profile can be a variance inextension length along the z-axis.

The coaptation regions can have a substantially hyperbolic profile. Eachof the plurality of leaflets can have a substantially ellipticalleaflet-stent attachment line. The stent can be an expandable,cylindrical stent. The leaflets can be reinforced with one or moreselected from the group consisting of: reinforcing materials anddirectional fibers. One or more selected from the group consisting of:coaptation regions and leaflet-stent attachment lines can be reinforcedwith one or more selected from the group consisting of: additionalpolymer thickness, reinforcing materials, and directional fibers.

Adjacent leaflets can be coupled to a wide post of the stent. The widepost can include one or more windows. The wide post can have a widthbetween about 0.5 mm and about 3 mm.

The stent can include metal or plastic. The metal can be selected fromthe group consisting of: stainless steel, 316L stainless steel,cobalt-chromium alloys, and nickel-titanium alloys.

The leaflets can be formed from a first polymer. The first polymer canbe selected from the group consisting of: polytetrafluoroethylene,polyethylene, polyurethane, silicone, and copolymers thereof.

The stent can be dip-coated in a second polymer. The second polymer canbe selected from the group consisting of: polytetrafluoroethylene,polyethylene, polyurethane, silicone, and copolymers thereof. Theleaflets can be coupled to the second polymer. The leaflets can bemechanically coupled to the second polymer. The leaflets can bechemically coupled to the second polymer. The leaflets can be coupled tothe second polymer by one or more techniques selected from the groupconsisting of: gluing, chemical fusing, thermal fusing, sonic welding,stitching, and mechanical fastening.

A leaflet-stent attachment line for each of the plurality of leafletscan substantially approximate a frame of the stent. The leaflet-stentattachment line can lie within about 3 mm of the frame of the stent.

The stent can include one or more anchor points. The anchor points cancontain a radio-opaque material.

The valve can be adapted and configured for replacement of one or morecardiac valves selected from the group consisting of: aortic, mitral,tricuspid, and pulmonary.

The valve can be adapted and configured for insertion in a subject'sveins in order to treat venous insufficiency. The valve can be adaptedand configured for serial expansion as the subject ages.

Another aspect of the invention provides an artificial, flexible valveincluding: a stent defining a wall and a plurality of leaflets extendingfrom the wall of the stent. Each of the plurality of leaflets terminatesin a commissure line. The commissure lines deviate from a hyperbolaformed in the x-y plane by at least one deviation selected from thegroup consisting of: a deviation in the z-direction and one or morecurves relative to the hyperbola.

This aspect of the invention can have a variety of embodiments. Theleaflets can further include extensions beyond the commissure linesalong a z-axis. The extensions can have a length along the z-axisbetween about 1 mm and about 10 mm. The extensions can have a curvedprofile. The curved profile can lie in an x-y plane. The curved profilecan be a variance in extension length along the z-axis.

Each of the plurality of leaflets can have a substantially ellipticalleaflet-stent attachment line. The stent can have an expandable,cylindrical stent. The leaflets can be reinforced with one or moreselected from the group consisting of: reinforcing materials anddirectional fibers.

One or more selected from the group consisting of: coaptation regionsand leaflet-stent attachment lines can be reinforced with one or moreselected from the group consisting of:

additional polymer thickness, reinforcing materials, and directionalfibers.

Adjacent leaflets can be coupled to a wide post of the stent. The widepost can include one or more windows. The wide post can have a widthbetween about 0.5 mm and about 3 mm.

The stent can include metal or plastic. The metal can be selected fromthe group consisting of: stainless steel, 316L stainless steel,cobalt-chromium alloys, and nickel-titanium alloys.

The leaflets can be formed from a first polymer. The first polymer canbe selected from the group consisting of: polytetrafluoroethylene,polyethylene, polyurethane, silicone, and copolymers thereof.

The stent can be dip-coated in a second polymer. The second polymer canbe selected from the group consisting of: polytetrafluoroethylene,polyethylene, polyurethane, silicone, and copolymers thereof. Theleaflets can be coupled to the second polymer. The leaflets can bemechanically coupled to the second polymer. The leaflets can bechemically coupled to the second polymer. The leaflets can be coupled tothe second polymer by one or more techniques selected from the groupconsisting of: gluing, chemical fusing, thermal fusing, sonic welding,stitching, and mechanical fastening.

A leaflet-stent attachment line for each of the plurality of leafletscan substantially approximate a frame of the stent. The leaflet-stentattachment line can lie within about 3 mm of the frame of the stent.

The stent can include one or more anchor points. The anchor points cancontain a radio-opaque material.

The valve can be adapted and configured for replacement of one or morecardiac valves selected from the group consisting of: aortic, mitral,tricuspid, and pulmonary.

The valve can be adapted and configured for insertion in a subject'sveins in order to treat venous insufficiency. The valve can be adaptedand configured for serial expansion as the subject ages.

Another aspect of the invention provides an artificial, flexible valveincluding: an expandable, cylindrical stent defining a wall and aplurality of leaflets extending from the wall of the stent. Adjacentleaflets can be coupled to a relatively wide post of the stent.

The leaflets can further include extensions beyond the commissure linesalong a z-axis. The extensions can have a length along the z-axisbetween about 1 mm and about 10 mm. The extensions can have a curvedprofile. The curved profile can lie in an x-y plane. The curved profilecan be a variance in extension length along the z-axis.

The coaptation regions can have a substantially hyperbolic profile. Eachof the plurality of leaflets can have a substantially ellipticalleaflet-stent attachment line. The leaflets can be reinforced with oneor more selected from the group consisting of: reinforcing materials anddirectional fibers.

One or more selected from the group consisting of: coaptation regionsand leaflet-stent attachment lines can be reinforced with one or moreselected from the group consisting of: additional polymer thickness,reinforcing materials, and directional fibers.

The relatively wide post can include one or more windows. The relativelywide post can have a width between about 0.5 mm and about 3 mm.

The stent can include metal or plastic. The metal can be selected fromthe group consisting of: stainless steel, 316L stainless steel,cobalt-chromium alloys, and nickel-titanium alloys.

The leaflets can be formed from a first polymer. The first polymer canbe selected from the group consisting of: polytetrafluoroethylene,polyethylene, polyurethane, silicone, and copolymers thereof.

The stent can be dip-coated in a second polymer. The second polymer canbe selected from the group consisting of: polytetrafluoroethylene,polyethylene, polyurethane, silicone, and copolymers thereof. Theleaflets can be coupled to the second polymer. The leaflets can bemechanically coupled to the second polymer. The leaflets can bechemically coupled to the second polymer. The leaflets can be coupled tothe second polymer by one or more techniques selected from the groupconsisting of: gluing, chemical fusing, thermal fusing, sonic welding,stitching, and mechanical fastening.

A leaflet-stent attachment line for each of the plurality of leafletscan substantially approximate a frame of the stent. The leaflet-stentattachment line can lie within about 3 mm of the frame of the stent.

The stent can include one or more anchor points. The anchor points cancontain a radio-opaque material.

The valve can be adapted and configured for replacement of one or morecardiac valves selected from the group consisting of: aortic, mitral,tricuspid, and pulmonary. The valve can be adapted and configured forinsertion in a subject's veins in order to treat venous insufficiency.The valve can be adapted and configured for serial expansion as thesubject ages. The valve may not contain any animal-derived materials.

Another aspect of the invention provides a mandrel including: acylindrical profile and a plurality of recesses adapted and configuredto define a plurality of leaflets forming a plurality of coaptationregions between two adjacent leaflets. The coaptation regions caninclude extensions along a z-axis and be adapted and configured to forma releasable, but substantially complete seal when the leaflets are in aclosed position.

This aspect of the invention can have a variety of embodiments. Themandrel can include one more cutting guides located between theplurality of recesses. The mandrel can include one or more heatingelements.

Another aspect of the invention provides a mandrel including: acylindrical profile and a plurality of recesses adapted and configuredto define a plurality of leaflets. Each of the plurality of leafletsterminate in a commissure line. The commissure lines deviate from ahyperbola formed in the x-y plane by at least one deviation selectedfrom the group consisting of: a deviation in the z-direction and one ormore curves relative to the hyperbola.

This aspect of the invention can have a variety of embodiments. Themandrel can include one more cutting guides located between theplurality of recesses. The mandrel can include one or more heatingelements.

Another aspect of the invention provides a method for fabricating anartificial, flexible valve. The method includes: dip coating acylindrical mandrel having a plurality of recesses each approximating aprofile of a leaflet and coupling the leaflets to an inner wall of astent.

This aspect of the invention can have a variety of embodiments. Themethod can further include dip coating the stent prior to coupling theleaflets to the inner wall of the stent. The stent and the mandrel canhave larger diameters than a target location for the valve. The methodcan further include separating adjacent leaflets from each other.

BRIEF DESCRIPTION OF THE DRAWINGS

For a fuller understanding of the nature and desired objects of thepresent invention, reference is made to the following detaileddescription taken in conjunction with the accompanying drawing figureswherein like reference characters denote corresponding parts throughoutthe several views and wherein:

FIGS. 1A and 1B provide perspective (in which fluid flows from thebottom of the stent toward the top of the stent) and top (in which fluidflows out of the page when the valve is open and flows down into thepage to close the valve) views of a valve according to an embodiment ofthe invention;

FIG. 2 depicts a stent according to an embodiment of the invention;

FIGS. 3A-3F depict various stent geometries according to embodiments ofthe invention;

FIG. 4 depicts various vertical post geometries according to embodimentsof the invention;

FIGS. 5A-5D depict the positioning of a leaflet joint adjacent to awindow of a vertical post according to an embodiment of the invention;

FIG. 6 depicts a stent prior to expansion, dip coating, and leafletinstallation according to an embodiment of the invention;

FIG. 7 depicts a stent including one or more anchor points according toan embodiment of the invention;

FIG. 8 depicts the engagement of a stent with a holder for dipping androtation according to an embodiment of the invention;

FIGS. 9A-9E depict a mandrel according to an embodiment of theinvention;

FIG. 9F depicts the positioning of a hyperbolic commissure line relativeto defined asymptotes according to embodiments of the invention;

FIG. 10A depicts a comparison of elliptical vs. parabolic geometriesleaflet valley lines according to embodiments of the invention;

FIGS. 10B and 10C depict a comparison of elliptical vs. parabolicleaflet stent attachment lines according to embodiments of theinvention;

FIGS. 11A-11D depict mandrels for forming coaptation regions of varyingheight according to embodiments of the invention;

FIGS. 12A-12D depict mandrels for forming coaptation regions of varyingradial length according to embodiments of the invention;

FIGS. 12E-12H depict mandrels for forming commissure lines havingvariable depths along the z-axis according to embodiments of theinvention;

FIGS. 121-12K depict mandrels for forming coaptation regions havingcurved profiles in an x-y plane, resulting in increased coaptationlength, according to embodiments of the invention;

FIGS. 12L-12N depict mandrels for forming commissure lines having curvedprofiles in an x-y plane, resulting in increased coaptation length,according to embodiments of the invention;

FIG. 13A depicts a mandrel according to an embodiment of the invention;

FIGS. 13B and 13C depict the positioning of reinforcing zones on amandrel according to an embodiment of the invention;

FIGS. 14A-14C depict various top profiles according to an embodiment ofthe invention;

FIGS. 15A and 15B depict the fabrication of valves according toembodiments of the invention;

FIG. 16 depict the fabrication of valves according to an embodiment ofthe invention;

FIGS. 17A and 17B depict the compression of a valve after assembly inorder to bring leaflets into contact with each other according toembodiments of the invention;

FIG. 17C is a high-speed photograph of a closed valve under pressureaccording to embodiments of the invention;

FIG. 18 depicts a method of implanting a valve according to embodimentsof the invention; and

FIG. 19 depicts a method of expanding an implanted valve according toembodiments of the invention.

DEFINITIONS

The instant invention is most clearly understood with reference to thefollowing definitions.

As used herein, the singular form “a,” “an,” and “the” include pluralreferences unless the context clearly dictates otherwise.

Unless specifically stated or obvious from context, as used herein, theterm “about” is understood as within a range of normal tolerance in theart, for example within 2 standard deviations of the mean. “About” canbe understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%,0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear fromcontext, all numerical values provided herein are modified by the termabout.

As used in the specification and claims, the terms “comprises,”“comprising,” “containing,” “having,” and the like can have the meaningascribed to them in U.S. patent law and can mean “includes,”“including,” and the like.

Unless specifically stated or obvious from context, the term “or,” asused herein, is understood to be inclusive.

Ranges provided herein are understood to be shorthand for all of thevalues within the range. For example, a range of 1 to 50 is understoodto include any number, combination of numbers, or sub-range from thegroup consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 (aswell as fractions thereof unless the context clearly dictatesotherwise).

DETAILED DESCRIPTION OF THE INVENTION

Aspects of the invention provide a novel platform that allowsdevelopment of polymeric valves of any size and shape. Aspects of theinvention can be applied to valves designed for surgical implantation(e.g., through a sternotomy or thoracotomy) or valves designed forpercutaneous, transcatheter implantation. Additionally, embodiments ofthe invention allow for possible percutaneous replacement of adysfunctional valve, whether in adults or in small children. Inaddition, if implanted in a child, embodiments of the invention allowthe valve to be serially expanded to accompany the child's growth.

Cardiac Applications

Multiple types of congenital heart defects require heart valvereplacement surgery in infancy or childhood. In adults, the mostcommonly replaced valves are aortic and mitral, whereas in children, thepulmonary valve is the most commonly replaced valve. Heart valves arecurrently replaced using tissue valves (homograft or xenograft) ormechanical metal valves, each having their shortcomings. Homograftvalves are in short supply, particularly in sizes suitable for use inchildren, and biologic tissue-based valves (whether bovine, porcine, orhomograft) tend to induce an immunologic reaction which leads to failureof these valves. Mechanical valves generally require anticoagulation,and are almost never used in the pulmonary position due to an increasedrisk of thrombosis.

Furthermore, none of the surgically implanted valves can adapt togrowing patients. The rapid growth of pediatric patients leads them tooutgrow their implanted valves within a few years and induces a cycle offrequent surgical valve replacements during childhood. Aspects of theinvention provide valves having improved biocompatibility, durability,and hemodynamic performance and would reduce the frequency of recurrentopen heart surgeries for valve replacement.

Venous Applications

Additionally, aspects of the invention can be used for venous valvereplacement in patients having venous disease such as chronic venousinsufficiency (leading to leg swelling). Because the polymer leafletscan be made extremely thin, the valves can even open under extremely lowvenous pressure gradients.

Artificial, Flexible Valves

Referring now to FIGS. 1A and 1B, one aspect of the invention providesan artificial, flexible valve 100. The valve includes an expandable,cylindrical stent 102 defining a wall 104. Valve 100 further includes aplurality of leaflets 106 a-106 c. Wall 104 can be formed by dip coatingstent 102 in a polymer as further described herein. Leaflets 106 can becoupled to wall 104 along seams 108 using a variety of approaches (e.g.,glue) as discussed further herein. Stent 102 can include one or morevertical posts 110, 112, which can be relatively narrow posts 110 orrelatively wide posts 112. Preferably leaflet joints between adjacentleaflets 106 are positioned on or close to a vertical post 110, 112 ofthe stent 102.

The valve 100 will now be described in the context of its components andmethods of fabrication.

Stents

Referring now to FIG. 2, stent 102 can be a metallic stent havingplurality of wires, strips, and the like 202 defining a plurality ofcells 204, 206 of various sizes. Stent 102 can be fabricated from avariety of malleable materials such as stainless steel, 316L stainlesssteel, cobalt-chromium alloys, nickel-titanium alloys (colloquiallyknown as “nitinol”), and the like. Stent 102 can also be formed fromvarious non-metallic materials such as plastics such as polyethylene,polyurethane, polytetrafluoroethylene (PTFE), silicone, poly(propylene)(PP), polyethylene terephthalate (PET), and the like.

Stent 102 can be completely enveloped by a polymer dip coating. Stent102 and/or wall 104 can also be fabricated from a biocompatiblematerial.

The stent 102 can be manufactured by laser cutting or wire forming. Toincrease bonding strength between metal and polymer, roughness of stentsurface can be controlled. Some or all open cells 204, 206 of the stentcan be covered as the bare 102 stent is dipped into the polymersolution.

FIG. 6 depicts a stent 102 prior to expansion, dip coating, and leafletinstallation. Stents 102 typically have a diameter of between about 2 mmand 6 mm prior to expansion and can be expanded to between about 5 mmand about 30 mm for implantation into a subject.

The components of stent 102 can have a variety of dimensions that can beselected to achieve a desired flexibility, rigidity, resilience, and thelike. For example, the thickness and width of components of the stent102 can be between about 0.1 mm and about 2 mm.

As discussed above, stent 102 can include one or more vertical posts 110a-110 c to enhance bonding with leaflets 106.

Stent 102 can include a plurality of vertical posts 110 that can serve avariety of functions. Some vertical posts 110 can include additionalstructure and are referred to herein as wide posts 112. Wide posts 112are preferably located at leaflet joints where two leaflets 106 meet.For example, in a valve 100 having a three leaflets 106, wide posts 112can be positioned at 120° intervals within cylindrical stent 102.

Wide posts 112 provide mechanical support to leaflets and prevent orsubstantially limit inward deformation of wall 104 due to tensile forcesapplied to leaflets 106 transferred to wall 104. Without being bound bytheory, it is believed that the wide posts 112 provide increasedstrength and resiliency due to formation of polymer wall 104 throughwindows 206 and around wide posts 112, thus providing cohesive holdingof the polymer to itself around the stent 102 instead of relying solelyon adhesive bonding of the polymer wall 104 to the stent 102.

Wide posts 112 advantageously allow for relaxed tolerances inpositioning leaflets 106 relative to wide posts 112. For example, window208 can have a width of between about 0.5 mm and about 3 min (e.g.,about 1 mm) and a height of between about 1 mm and about 10 mm (e.g.,about 5 mm).

A variety of additional wide post geometries are depicts in FIGS. 3A-3F.In FIG. 3A, the wide posts have a solid architecture without anywindows. In FIG. 3B, the wide posts have a substantially rectangulararchitecture defining a single, long window as in FIGS. 1A, 1B, and 2.In FIG. 3C, the wide posts define a plurality of coaxial substantiallyrectangular windows. In FIG. 3D, the wide posts define a plurality ofcoaxial, substantially parallel windows. In FIG. 3E, the wide postsdefine a plurality of coaxial, substantially rectangular windows in a2×3 arrangement. In FIG. 3F, the wide posts include a plurality ofcircular windows. These wide post architectures are further depicted inFIG. 4. Although substantially circular and rectangular windowgeometries are depicted, any geometry can be utilized including windowshaving a profile approximating a triangle, a square, an n-gon (e.g., ahexagon, an octagon, and the like), and the like.

Referring now to FIGS. 5A-5D, the positioning of a leaflet joint 502(formed, e.g., on mandrel 900 as discussed herein) adjacent to window206 of wide post 112 is depicted. (The polymer dip-coated wall 104 iscompletely transparent for case and clarity in viewing, but can betransparent, translucent, or opaque.) FIG. 5B-5D further depict how ageometry of the stent 102 can be selected to substantially approximatethe leaflet-stent attachment seam 108 discussed herein in order toprovide added mechanical support and resiliency.

Referring now to FIG. 7, stent 102 can include one or more anchor points702. Anchor points 702 advantageously facilitate holding, dipping, androtation of the stent 102 during the dip coating process withoutinterfering with the dip coating of the remainder of the stentarchitecture. Accordingly, the entire stent 102 can be dip coated in asingle dipping, although multiple dippings can be utilized to controlcoating density, thickness, and the like. Anchor points 702 can alsoreceive one or more radio-opaque materials such as platinum to aid inplacement and visualization of the valve.

In one embodiments depicted in FIG. 8, stent 102 can be engaged with aholder 802 (e.g., by posts 804) for dipping and rotation. Once thepolymer (again depicted as, but not necessarily, transparent) is wet onthe stent 102, the stent can be positioned horizontally and rotatedaxially.

Leaflets

Leaflets 106 can be formed using a variety of techniques including dipcoating, 3D-printing (also known as additive manufacturing), molding,and the like.

Referring now to FIG. 9A, leaflets 106 can be fabricated by dip coatinga mandrel 900 with a polymer. The mandrel 900 can be made with a solidsuch as a metal (e.g., stainless steel, titanium, aluminum, and thelike), a plastic (e.g., polyethylene, polypropylene, polyvinyl chloride,polytetrafluoroethylene, polyoxymethylene, and the like), and the like.Since the coated polymer leaflets 106 will be removed from the mandrel900 after the polymer dries, roughness of mandrel surface can becontrolled using known machining and other manufacturing techniques. Themandrel 900 can be made from a cylinder. Preferably, the diameter of themandrel 900 is a slightly (e.g., between about 0.05 and about 0.4 mm)smaller than inner diameter of stent 102 after expansion.

The mandrel 900 for the leaflets 106 can have novel features, includingedges representing the leaflet attachment points that are mathematicallydefined and leaflet tips that are extended in order to increase thecoaptation length of the leaflets. The mandrel 900 can be dimensioned toproduce leaflets 106 having different regional thickness andsupplementary materials such as directional fibers or reinforcingparticles inserted between layers or mixed into the polymer solution inorder to increase durability. For example, polymer interaction withparticles on the nanoscale or microscale can greatly improve thephysical properties or tear resistance of the polymer leaflets 106.

Mandrel 900 can be designed to have a complementary geometry to thedesired leaflet shape and permits easier viewing of leaflet geometry.Although mandrel 900 is utilized to describe the geometry of the leaflet106, it should be recognized that the upstream surface of the resultingleaflets will have this geometry when formed by dip coating and that thecomplementary geometry of the leaflet(s) 106 can be produced usingtechniques other than dip coating. Mandrel 900 is preferably cylindricaland can have an outer profile substantially approximating an innerprofile of stent 102. Mandrel 900 can define a plurality of pockets 902that each define a leaflet 106 as it hangs from wall 104 via attachmentline 108. Each leaflet 106 terminates in a commissure line 904 often,but not necessarily lying in a plane at the point where the ellipticalor parabolic curve ends and where the leaflet often contacts the otherleaflets. A substantially vertical coaptation region 906 can extendbeyond the commissure line 904 to an extended commissure line 912 forimproved sealing as will be discussed herein.

Referring now to FIGS. 9B and 9C, mandrel can be cast, machined,printed, or otherwise fabricated so that pockets 902 have a desiredgeometry. In one embodiment of the invention, the commissure line 904(and optionally the coaptation region 906 and extended commissure line912) has a substantially hyperbolic profile when viewed in the x-yplane. Additionally or alternatively, leaflet-stent attachment line 108and/or a leaflet valley line 908 (formed by taking a cross-section in az plane) can have substantially elliptical profiles. Although otherquadratic profiles (e.g., parabolic) could be used, elliptical profilesbetter promote a secure pocket shape and the closure of theleaflet-stent attachment line 108 to the contour of the cylindricalmandrel 900. A comparison of elliptical vs. parabolic leaflet valleylines is provided in FIG. 10A. A comparison of elliptical vs. parabolicleaflet-stent attachment lines is provided in FIGS. 10B and 10C.

Referring now to FIG. 9D, mandrel 900 can define a gap 910 betweenadjacent leaflets. Advantageously, leaflets 106 with a hyperbolicprofile can produce smaller gaps than leaflets with parabolic profiles.For example, gaps 910 can be less than 1 mm or between about 0.1 mm andabout 1 mm (e.g., between about 0.1 mm and about 0.2 mm, between about0.2 mm and about 0.3 mm, between about 0.3 mm and about 0.4 mm, betweenabout 0.4 mm and about 0.5 mm, between about 0.5 mm and about 0.6 mm,between about 0.6 mm and about 0.7 mm, between about 0.7 mm and about0.8 mm, about 0.8 mm and about 0.9 mm, about 0.9 mm and about 1 mm, andthe like).

As seen in FIG. 9E, the length of hyperbolic commissure line 904 isabout twice the radius of the stent or mandrel. The positioning of ahyperbolic commissure line 904 relative to defined asymptotes isdepicted in FIG. 9F.

Referring now to FIG. 11A, coaptation region can have minimal height inthe z-axis so as to consist only of the commissure line 904.Alternatively, coaptation region 906 can have a vertical extension inthe z-axis to an extended commissure line 912 as depicted in FIGS.11B-11D. The height of the coaptation region 906 can be selected toreduce the amount of regurgitation, while still allowing the valve toopen. For example the coaptation region 906 can have a height betweenabout 1 mm and about 10 mm (e.g., about 3 mm). Although FIGS. 11B-11Ddepict extensions of coaptation region 904 that extend solely in thez-axis, the same effect can be achieved using a smooth leaflet-stentattachment line that extends in the z-axis so that the adjacentleaflet-stent attachment lines (and/or the regions of lealets hangingtherebetween) approach and/or contact each other to form an extendedcoaptation region.

The zone of coaptation is affected by the pressure placed upon theclosed valve 100. The higher the pressure, the more downward tension isplaced on the leaflets 106, possibly leading to a failure of coaptationwith consequent regurgitation. Proper coaptation also allows theleaflets 106 to support each other, so there is less stress placed onany individual leaflet 106. Another benefit of enhancing height of thecoaptation zone is that this allows the valve 100 to be re-dilated to alarger diameter late after implantation (such as to accommodate growthof a pediatric patient), while still maintaining competence of the valve100.

Options for enhancing the height of the coaptation zone include creatingexcess length of the leaflet free edges, so that the free edge length isgreater than twice the radius of the stent or mandrel depicted in FIG.9E. Lengthening of the leaflet free edges can be accomplished by curvededges in the x-y plane, or in the z-axis, or in all 3 axes.

Referring now to FIGS. 12A-12D, coaptation regions 906 can have varyingheights in the z-axis between the commissure line 904 and extendedcommissure line 912. For example, the height of coaptation region 906can increase toward the outside of the mandrel as depicted in FIG. 12B.In another embodiment, the height of the coaptation region 906 can dipto form a trough between the outside and the center of the mandrel 900as depicted in FIG. 12C.

Referring now to FIGS. 12E-12H, the same profiles can be applied tocommissure line 904 without any coaptation region 906.

Referring now to FIGS. 121-12K, the commissure lines 904, coaptationregions 906 and/or extended commissure lines 912 can have curvedprofiles in an x-y plane (as opposed to a substantially hyperbolicprofile) in order to increase the length of the commissure line 904,coaptation region 906, and/or extended commissure line 912. For example,the mandrel 900 can be thicker between the perimeter and the center asdepicted in FIG. 121 to produce one or more scallops. In FIGS. 12J and12K, the mandrel 900 can have either a single curve or multiple curves.

Referring now to FIGS. 12L-12N, the same profiles can be applied tocommissure line 904 without any coaptation region 906.

In order to increase tear-resistance of the leaflets 106 and enhancebonding strength between leaflets 106 and stent 102, the thickness ofthe leaflets 106 can be controlled regionally. Because the most commonfailure points are at the outer edges of the leaflets 106 (such ascommissure line 904 or extended commissure line 912 and leaflet-stentattachment line 108), increased thickness at outer areas of the leaflets106 can improve the strength and durability. Also, if local areas areexpected to have concentrated stress, the areas can be locallyreinforced (e.g., made thicker than other areas). The thickness can besmoothly increased. The width of thickened area along leaflet-stentattachment line 108 can be large enough to cover the glued area forbonding the leaflets 106 and the covered stent 102. In some embodiments,the thickness of thickened areas of the leaflets is between about 0.1 mmand about 1 mm.

Multiple dippings can be performed to produce leaflets with a desiredthickness. In some embodiments, the thickness of the leaflets is betweenabout 0.01 mm and about 0.2 mm.

Different reinforcing materials such as strips, fibers and particles canbe placed between the layers, or directly mixed into the polymersolution. The inserted material(s) can prevent tearing and reducepropagation of the tear if it occurs. The materials can have directionalproperties and can be layered onto, or embedded into, the leaflets in anoptimal direction to prevent or limit tears.

Referring now to FIG. 13A, a photograph of a mandrel 900 is provided.Referring now to FIG. 13B, a reinforcing zone 1302 can be formed on themandrel 900 prior either by removing mandrel material to allow foradditional thickness in certain (e.g., outer) regions of leaflets 106 orby introducing one or more reinforcing fibers prior to, during, or afterdip coating. Suitable reinforcing materials include fibers (e.g.,polymers, nanotubules, aramids, para-aramids, and the like), wires, andthe like. Transitions between reinforced and non-reinforced areas can besmooth in order to minimize any turbulence in the implanted valve 100.

After dipping the mandrel 900 into the polymer solution, the coatedpolymer dries in order to form the leaflet(s) 106. Because the formedleaflets 106 are connected, they need to be separated from each other.These can be cut by a sharp cutter (e.g., a knife, a scalpel, a razorblade, a utility knife, and the like), a heated iron, a laser, a rotarytool, and the like. A guide on the top surface of the mandrel forcutting provides a clear, easy, and safe cutting path. The guide can begrooved/concave or convex. Also, the commissure edges of the mandrel canbe sharp like a blade to facilitate leaflet separation and to improve onthe quality of the cut edges.

Referring now to FIG. 14A-14C, the gap portion 910 of the mandrel canhave various top profiles to facilitate sealing of the leaflets and/orseparation of the leaflets prior to removal from mandrel 900. Forexample, the gap portion 910 can have a grooved profile as depicted inFIG. 14A, a concave profile as depicted in FIG. 14B, or an angledprofile as depicted in FIG. 14C. Additionally or alternatively, aheating element (e.g., an Ohmic or resistive heating element such as awire) can be included in the mandrel and can be actuated to melt thepolymer to separate the leaflets and/or relax the polymer to facilitateremoval of the leaflets from the mandrel 900.

The stent-mounted valve 100 can be implanted with smaller diameter thanits manufactured diameter for reducing leakage and improving durability.

Methods of Fabricating Valves

Referring now to FIGS. 15A, 15B, and 16, a method for fabricating avalve is depicted. A bare stent 102 and a bare mandrel 900 are provided.

In some embodiments, the stent 102 can be first coated with a polymersuch as PEEK or other metal surface modifier prior to further dipcoating of the stent 102 in another polymer in order to improve adhesionof the leaflet polymer 106 to the metal stent 102.

The bare mandrel 900 can optionally be coated with a release agent topromote separation of the polymer leaflets from the mandrel 900.

Both the bare stent 102 and the mandrel 900 are dip coated separately ina polymer, which may be the same or different for the bare stent 102 andthe mandrel 900.

The leaflets 106 formed on the mandrel 900 can be removed prior tointroduction to the coated stent. Alternatively, the coated mandrel 900can be introduced into the coated stent, the leaflets 106 can be bondedto the coated stent, and the mandrel 900 can be then be removed to leavethe assembled valve 100.

Leaflets 106 can be bonded to the dip-coated stent using a variety oftechniques including gluing, chemical fusing (i.e., dissolving thepolymers) thermal fusing, sonic welding, stitching, mechanicalfastening, and the like. For example, the same polymer solution used tocoat either bare stent 102 and/or mandrel 900 can be applied to bond theleaflets 106 to the dip-coated stent.

Although separate fabrication of the polymer-coated stent and theleaflets 106 are currently preferred as a means of avoiding orminimizing air bubbles, the entire valve could be formed in a single dipcoating (or series of dip coatings) through use of production-grademanufacturing techniques and other optimizations.

Although dipcoating was successfully used to fabricate prototypes of thevalves described herein, any other manufacturing technique capable ofproducing flexible leaflets can be utilized. Exemplary techniquesinclude injection molding and additive manufacturing or 3D printing.Referring now to FIGS. 17A and 17B, stent 102 and leaflets 106 can befabricated based on a diameter that is slightly larger than theplacement location as depicted in FIG. 17A. When deployed to a locationhaving a smaller diameter than the manufactured diameter, the leaflets106 will be held in tight contact with each other as seen in FIG. 17B toform a tight seal. (In order to form a press fit with the vessel wall,the deployed diameter will be greater than the vessel diameter, but lessthan the manufactured diameter.)

As can be seen in FIGS. 17A and 17B, the coaptation regions of leaflets106 have a substantially hyperbolic profile both at the manufactureddiameter and the deployed diameter.

Referring now to FIG. 17C, a high-speed photograph of a closed valveunder pressure during in vitro testing in a hemodynamic pulse duplicatoris provided.

Polymers

The leaflets 106 can be formed from the same or different polymer withwhich the stent 102 is coated to form wall 104. For example, theleaflets 106 can be formed from polymers such as polyethylene,polyurethane, silicone, and the like. Wall 104 can be formed frompolyethylene, polyurethane, silicone, and the like.

Supplementary materials such as directional fibers can mixed into thepolymer solution or applied to the leaflets between coatings in order toincrease durability

The selected polymer can be dissolved by a solvent such astetrahydrofuran or dimethylacetamide. The thickness of the coatedpolymer can be controlled as a function of the density of the polymersolution and total number of dippings. When the polymer becomes dryafter dipping, the coated stent and mandrel can be placed horizontallyand axially rotated in order to produce a constant thickness and preventthe polymer from dripping.

Implantation of Valves

Referring now to FIG. 18, a method 1800 of implanting an artificialvalve is provided. The valve to be implanted can be a valve 100 asdescribed herein.

In step S1802, the valve is placed over an expander and within a sheath.Various surgical expanders and access devices exist in the cardiacsurgery field. For example, a balloon catheter could be introduced intoa patient's femoral artery and guided to the location of the implantedvalve (e.g., within the patient's heart or systemic veins).

In step S1804, the sheath (containing the valve and the expander) isintroduced into a vessel of the subject.

In step S1806, the valve and the expander are advanced from the sheathand positioned in the desired location.

In step S1808, the desired positioning can be verified using variousimaging techniques such as fiber optics, ultrasound, X-ray, and thelike.

In step S1810, the expander is actuated within the valve to expand thevalve to form a press fit against the vessel in which the valve isimplanted. For example, a balloon catheter can be expanded byintroducing gas or a liquid into the balloon.

In step S1812, the desired positioning and expansion can be verifiedusing various imaging techniques such as fiber optics, ultrasound,X-ray, and the like.

In step S1814, the expander and sheath can be retracted according tostandard surgical techniques.

Expansion of Implanted Valves

Referring now to FIG. 19, a method 1900 of expanding an implanted valveis provided. The implanted valve can be a valve 100 as described herein.

In step S1902, an expander is introduced into the implanted valve.

In step S1904, the expander is actuated within the implanted valve toincrease the diameter of the implanted valve.

In step S1906, the desired expansion can be verified using variousimaging techniques. In step S1908, the expander can be retractedaccording to standard surgical techniques.

Surgically-Implanted Valves

Although embodiments of the invention are described and depicted in thecontext of percutaneous, transcatheter valves having expandable,cylindrical stents, embodiments of the invention described herein can beapplied to surgically-implanted valves that generally include anchorshaving fixed-diameter anchors supporting a plurality of leaflets (e.g.,the CARPENTIER-EDWARDS™ series of valves available from EdwardsLifesciences Corporation of Irvine, Calif.). In such embodiments, theanchor replaces the expandable, cylindrical stents described herein.

EQUIVALENTS

Although preferred embodiments of the invention have been describedusing specific terms, such description is for illustrative purposesonly, and it is to be understood that changes and variations may be madewithout departing from the spirit or scope of the following claims.

INCORPORATION BY REFERENCE

The entire contents of all patents, published patent applications, andother references cited herein are hereby expressly incorporated hereinin their entireties by reference.

1-100. (canceled)
 101. An artificial valve, comprising: an expandableframe configured to be implanted within a patient, the expandable framehaving a maximum radial extent when the expandable frame is in afully-expanded configuration in which the valve is in a maximum workingcondition; and a plurality of leaflets disposed within and coupled tothe frame, each leaflet from the plurality of leaflets extending fromthe frame and terminating at a free edge, each free edge having a lengththat is greater than the maximum radial extent of the expandable framewhen the expandable frame is in its fully-expanded configuration. 102.The artificial valve of claim 101, wherein a first leaflet from theplurality of leaflets is coupled to a first portion of the frame and asecond portion of the frame, a distance along the free edge of the firstleaflet between the first portion of the frame and the second portion ofthe frame being greater than an are distance along the frame between thefirst portion and the second portion.
 103. The artificial valve of claim101, wherein the expandable frame has a first end, a second end, and alongitudinal z-axis defined therebetween, the plurality of leafletsforming a coaptation region having a maximum radial extent in which theleaflets (1) coapt sufficiently to prevent fluid flow along thelongitudinal z-axis in a first direction and through the coaptationregion, and (2) allow fluid flow along the longitudinal z-axis in asecond direction opposite the first direction, the coaptation regionhaving a radial extent less than the maximum radial extent when theframe is in a partially-expanded configuration such that the pluralityof leaflets coapt sufficiently to prevent fluid flow along thelongitudinal z-axis in the first direction and through the coaptationregion, and (2) allow fluid flow along the longitudinal z-axis in thesecond direction.
 104. The artificial valve of claim 101, wherein eachfree edge forms a portion of the coaptation region and the leaflet freeedges collectively provide a tortuous path for fluid flow to preventfluid flow in the predefined direction.
 105. The artificial valve ofclaim 101, wherein each leaflet has a variable thickness in which itsthickness is reduced from its attachment to the expandable frame towardsits free edge.
 106. The artificial valve of claim 101, wherein the freeedge of each leaflet varies along a longitudinal z-axis of theexpandable frame when the expandable frame is in the fully-expandedconfiguration.
 107. The artificial valve of claim 106, wherein thelongitudinal z-axis of the expandable frame is defined between a firstend of the expandable frame and a second end of the expandable frame,the plurality of leaflets being configured to allow fluid flow from thefirst end to the second end and restrict fluid flow from the second endto the first end.
 108. The artificial valve of claim 101, wherein theplurality of leaflets are formed of polymer.
 109. The artificial valveof claim 101, wherein each leaflet from the plurality of leaflets iscoupled to the frame along a leaflet attachment line, the leafletattachment line including a conic portion and a linear portion extendingfrom a point at which the conic portion terminates to the free edge ofthe leaflet.
 110. The artificial valve of claim 101, wherein the maximumworking condition is a condition in which the expandable frame isexpanded to its largest possible diameter that allows sufficientcoaptation between the plurality of leaflets.
 111. An artificial valve,comprising: an expandable frame configured to be implanted within apatient, the expandable frame having a maximum radial extent when theexpandable frame is in a fully-expanded configuration in which the valveis in a maximum working condition; and a plurality of leaflets disposedwithin and coupled to the frame, each leaflet from the plurality ofleaflets extending from the frame and terminating at a free edge, eachfree edge varies along a longitudinal z-axis of the expandable framewhen the expandable frame is in its fully-expanded configuration. 112.The artificial valve of claim 111, wherein the longitudinal z-axis ofthe expandable frame is defined between a first end of the expandableframe and a second end of the expandable frame, the plurality ofleaflets being configured to allow fluid flow from the first end to thesecond end and restrict fluid flow from the second end to the first end.113. The artificial valve of claim 111, wherein a first leaflet from theplurality of leaflets is coupled to a first portion of the frame and asecond portion of the frame, a distance along the free edge of the firstleaflet between the first portion of the frame and the second portion ofthe frame being greater than an are distance along the frame between thefirst portion and the second portion.
 114. A mandrel, comprising: acylindrical profile having a plurality of recesses configured to definea plurality of valve leaflets, the plurality of recesses each (1)extending from a valve attachment line and (2) terminating at acommissure line, each commissure line having a length greater than adiameter of the cylindrical profile.
 115. The mandrel of claim 114,wherein: each commissure line varies along a longitudinal z-axis of thecylindrical profile.
 116. The mandrel of claim 114, wherein eachcommissure line is a first commissure line, each valve attachment linebeing curved until reaching a second commissure line that is definedbetween the attachment line and the first commissure line, a coaptationregion being defined by and linearly extending between the firstcommissure line and the second commissure line.
 117. The mandrel ofclaim 114, wherein each valve attachment line includes a conic portionand a linear portion that extends from a point at which the conicportion terminates to the commissure line.
 118. The mandrel of claim114, wherein the commissure line extends from the linear portion towardsa center of the cylindrical profile, the commissure line varying inheight.
 119. The mandrel of claim 114, wherein the commissure lineextends from the linear portion towards a center of the cylindricalprofile, the commissure line varying along a longitudinal z-axis of thecylindrical profile.
 120. A frame for an artificial valve, comprising:an expandable cylindrical body having a first end, a second end, and alongitudinal z-axis extending therebetween; and a plurality of valveleaflets, the expandable cylindrical body being formed by a plurality ofposts extending substantially parallel to and circumferentially aboutthe longitudinal z-axis, the plurality of posts including a first set ofposts having a first width and a second set of posts having a secondwidth that is greater than the first width, the first set of postsdefining a plurality of open cells therebetween that are variable inshape during expansion of the expandable cylindrical body, each postfrom the second set of posts being disposed at a junction between andcoupled to two valve leaflets from the plurality of valve leaflets. 121.The frame of claim 120, wherein each post from the second set of postsdefines one or more windows configured to have a fixed shape duringexpansion of the expandable cylindrical body.
 122. The frame of claim121, wherein the second set of posts includes polymer within its one ormore windows, each post from the second set of posts being coupled tothe two valve leaflets via the polymer.
 123. The frame of claim 120,wherein the plurality of open cells are covered.
 124. The frame of claim120, wherein the plurality of open cells are coated with a polymer. 125.The frame of claim 120, wherein the plurality of windows have a width ofabout 0.5 mm to about 3 mm, and a height of about 1 mm to about 10 mm.126. The frame of claim 121, wherein the one or more windows aresubstantially rectangular.
 127. The frame of claim 120, wherein thesecond set of posts consists of three posts each of which arecircumferentially positioned at 120 degree intervals among theexpandable cylindrical body, the plurality of valve leaflets consistingof three valve leaflets.
 128. The frame of claim 120, wherein theplurality of valve leaflets are coupled to the second set of posts viaat least one of a chemical coupling technique, chemical fusing, thermalfusing, or sonic welding.
 129. The frame of claim 128, wherein theplurality of valve leaflets are formed of a polymer.
 130. The frame ofclaim 120, wherein the entire external surface of the expandablecylindrical body is coated with a polymer.